Regulation of CYP4A genes by peroxisome proliferator activated receptors

The peroxisome proliferator activated receptor a (PPARa), a nuclear receptor, mediates the induction of P450 4As by peroxisome proliferators. PPARs bind as heterodimers with the retinoid X receptor α (RXRα) to a tripartite, transcriptional enhancer (PPRE) that contains two imperfect zinc finger DNA binding sites separated by a single nucleotide (DR1 Motif). PPARα binds to the upstream site and a 5′ extension similar to that recognized by Rev-ErbA monomers. Features of PPREs favor the binding of PPARs in preference to other nuclear receptors. However, the expression of PPARa is relatively low in human liver resulting in an unfavorable ratio relative to other proteins that recognize PPREs. This may contribute to the refractivity of human liver to P450 4A induction. PPARs α, δ and γ differ in their tissue distribution and ligand specificity. Ligands include xenobiotics and endogenous compounds such as fatty acids and prostaglandins. Our studies indicate that 8R, 9R-dihydroxytetraeicosatrienoic acid is a relative high affinity ligand for PPARa. This compound is produced by the actions of P450s and epoxide hydrase in tissues in which PPARα is prominently expressed.